Successful lung transplant in rapid progressive interstitial lung disease associated with anti-melanoma differentiation associated gene 5

Successful lung transplant can be achieved in anti-MDA5 DM patients with RP-ILD requiring ECMO. Sir, Anti-melanoma differentiation associated gene 5 (MDA5) has emerged as an important myositis-specific antibody that is seen in 10–35% of patients with DM [1]. Patients with anti-MDA5 antibody are more likely to have clinical amyopathic DM (CADM), a term coined to describe absent or minimal muscle disease, and to have increased risk of interstitial lung disease (ILD) [2]. Asian patients with anti-MDA5 have higher frequency of ILD and especially rapid progressive ILD (RP-ILD) leading to high mortality up to 50–60% within 6 months [2]. Western literature has conflicting data on anti-MDA5 association with RP-ILD [1, 3]. Here we present a case series of four anti-MDA5 DM patients with RP-ILD on mechanical ventilation who successfully underwent bilateral lung transplantation. This report was approved by Vancouver Coastal Health and University of British Columbia Research Ethics Board (H18-03216). Individual patient consent is waived by the institution. Vancouver General Hospital is the single transplant centre in the province of British Columbia, Canada. From 2014 to 2018, we had a total of 18 cases of confirmed anti-MDA5 DM in British Columbia. RP-ILD was found in nine patients. Four patients with RP-ILD were initiated on extracorporeal membrane oxygenation (ECMO) support and received double lung transplants, after maximal immunosuppressive therapy and prolonged mechanical ventilation for respiratory failure. All four patients had very aggressive lung disease and required intubation within 2–4 months from first symptom onset. They all had typical DM rash and some had ulcerative skin lesions. Three of the four patients were amyopathic. Their cutaneous and muscular clinical features at presentation are summarized in Table 1. Clinical courses of the four anti-MDA5 DM patients with RP-ILD who had successful lung transplant Myositis antibody testing was done with line immunoassay (Euroimmun GmbH, Lübeck, Germany). CK: creatine kinase; CMV: cytomegalovirus; ECMO: extracorporeal membrane oxygenation; F:females; IV CYC: intravenous CYC; GC: glucocorticoid; M: males; MMF: mycophenolate; PE: pulmonary emboli; Tac: tacrolimus; RP-ILD: rapid progressive interstitial lung disease; RTX: rituximab; UGIB: upper gastrointestinal bleed. Clinical courses of the four anti-MDA5 DM patients with RP-ILD who had successful lung transplant Myositis antibody testing was done with line immunoassay (Euroimmun GmbH, Lübeck, Germany). CK: creatine kinase; CMV: cytomegalovirus; ECMO: extracorporeal membrane oxygenation; F:females; IV CYC: intravenous CYC; GC: glucocorticoid; M: males; MMF: mycophenolate; PE: pulmonary emboli; Tac: tacrolimus; RP-ILD: rapid progressive interstitial lung disease; RTX: rituximab; UGIB: upper gastrointestinal bleed. All four patients survived the transplant and eventually were discharged in a stable condition. One patient (no. 3) passed away from infectious complications 14 months after transplant. At the time of final follow-up (range from 12 to 32 months), the other three patients had no recurrent cutaneous disease and enjoyed normal muscle strength. Patient 1 had normal pulmonary function test while patients 2 and 4 had mildly restrictive lung function. All were on room air living independently in the community. The clinical courses of these patients are summarized in Table 1. To our knowledge, this is the first and largest case series describing successful lung transplantation in anti-MDA5 DM patients with RP-ILD while on ECMO support. We recently published a case series of 21 Canadian anti-MDA5 DM patients [3]. Prior to this study, successful lung transplants in anti-MDA5 DM-associated RP-ILD were reported in two cases only. The first case was a 52-year-old Japanese female who received a left lower lobe from her daughter and a right lower lobe from her son within 15 days of hospitalization. She remained well on immunosuppression (not specified) [4]. Most recently, Karolinska clinicians reported a 38-year-old Caucasian man who had a successful lung transplant after failing glucocorticoid and CYC [5]. This patient remained well in remission at 12 years’ follow-up. Two other case reports also demonstrated excellent transplant outcome in DM-associated RP-ILD, one with anti-Jo-1 [6] and the other with an unknown antibody profile [7]. Evidence for treatment outcomes of RP-ILD associated with anti-MDA5 is scarce and based on case reports only. A recent multicentre prospective study from Japan showed that an early combined regimen of high-dose glucocorticoid, tacrolimus and intravenous CYC improved survival significantly to 89% at 6 months, compared with 33% from the traditional step-up regimen group (i.e. glucocorticoid first and stepwise addition of immunosuppressants) [8]. Although the aggressive immunosuppressive combination is more effective, patients with this disease still face high mortality, at least in Asians [8]. Traditionally, the outcomes of lung transplantation in patients requiring pretransplant ECMO were poor, which reflected the severity of the pretransplant condition as well as further decondition while receiving ECMO. Therefore, understandably, transplant clinicians tend to reserve scarce lung resources to those not on ECMO. Furthermore, there are considerable concerns of theoretical recurrence of ILD in the transplanted lungs secondary to the underlying connective tissue disease. However, in our case series, ECMO bridging to lung transplant was the only life-saving intervention for those who further deteriorate from hypoxia despite maximal immunosuppression and mechanical ventilation support. It is important for clinicians to be aware of ECMO as a modality to bridge to lung transplant as it is not available in many centres globally. In three of the four patients, we have long-term data confirming no recurrent lung disease after lung transplant. This is the largest case series demonstrating successful lung transplant can be achieved in patients with RP-ILD secondary to anti-MDA5 DM requiring ECMO for oxygenation. Based on our local experience, we recommend consulting a transplant team early for assessment. Following transplant, maintenance therapy with glucocorticoid, mycophenolate and tacrolimus, for both transplant anti-rejection and autoimmune ILD, seems appropriate. We thank Drs Kamran Shojania, Roland Nador and John Yee for the excellent care to the patients included in this study and constructive feedback on the manuscript. Funding: No specific funding was received from any funding bodies in the public, commercial or not-for-profit sectors to carry out the work described in this manuscript. Disclosure statement: The authors have declared no conflicts of interest.

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